Multi-particulate form of medicament, comprising at least two differently coated forms of pellet

ABSTRACT

The invention relates to a multiparticulate drug form suitable for uniform release of an active pharmaceutical ingredient in the small intestine and in the large intestine, comprising at least two forms of pellets A and B which comprise an active pharmaceutical ingredient in the core and have different polymer coatings which determine the release of the active ingredient at different pH values, characterized in that pellet form A is provided with an inner polymer coating which enables continuous release of active ingredient, and has an outer enteric coating which rapidly dissolves above about pH 5.5, and pellet form B is provided with a polymer coating which, in the USP release test, releases less than 20% of the active ingredient at pH 6.8 in 6 hours and releases more than 50% of the active ingredient at pH 7.2 in 6 hours. The invention additionally relates to a process for producing the multiparticulate drug form and to the use of pellet forms A and B for producing the drug form.

The invention relates to a multiparticulate drug form which comprises atleast two differently coated pellet forms and enables release of activeingredient to be substantially uniform over the entire intestinalregion. The invention further relates to a process for producing themultiparticulate drug form and to the use of the pellet forms A and Bfor producing the drug form.

PRIOR ART

Multiparticulate drug forms obtained by compression of a binder withactive ingredient-containing pellets coated with (meth)acrylatecopolymers resistant to gastric juice are disclosed in Beckert et al.(1996), “Compression of enteric-coated pellets to disintegratingtablets” International Journal of Pharmaceuticals 143, pp. 13-23.

(Meth)acrylate copolymers which comprise monomers with quaternaryammonium groups, e.g. trimethylammoniumethly [sic] methacrylatechloride, and their use for release-slowing medicament coatings havebeen known for a long time (for example from EP-A 181 515 or from DE-C 1617 751). Processing takes place in organic solution or as aqueousdispersion, for example by spraying onto medicament cores or elsewithout solvent in the presence of flow aids by application in the melt(see EP-A 0 727 205).

EP-A 629 398 describes pharmaceutical formulations which have a corewith an active ingredient and an organic acid, where the core has atwo-layer covering. The inner covering in this case is formed by arelease-slowing (meth)acrylate copolymer with quaternary ammonium groups(EUDRAGIT® RS), while the outer covering has an enteric coating, forexample a copolymer of the type EUDRAGIT® L30D-55 (ethylacrylate/methacrylic acid, 50:50). The release characteristics achievedcan be described by a rapid release of active ingredient after a timelag at elevated pH.

EP 0 704 207 A2 describes thermoplastic materials for drug coveringssoluble in intestinal juice. These comprise copolymers of 16 to 40% byweight acrylic or methacrylic acid, 30 to 80% by weight methyl acrylateand 0 to 40% by weight of other alkyl esters of acrylic acid and/ormethacrylic acid.

EP 0 704 208 A2 describes coating agents and binders for drug coveringssoluble in intestinal juice. These comprise copolymers of 10 to 25% byweight methacrylic acid, 40 to 70% by weight methyl acrylate and 20 to40% by weight methyl methacrylate. The description mentions not onlymonolayer coatings but also multilayer coating systems. These mayconsist of a core which comprises, for example, a basic or awater-sensitive active ingredient, have a sealing layer of anothercoating material such as cellulose ether, cellulose ester or a cationicpolymethacrylate, for example of the EUDRAGIT® type, inter aliaincluding EUDRAGIT® RS and RL, and are then additionally provided withthe abovementioned covering soluble in intestinal juice.

Multiparticulate drug forms in the form of capsules or compressedtablets have been known for some time. It is also known to introducepellets with different polymer coatings into multiparticulate drug formsin order in this way to achieve combined release profiles.

Problem and Solution

There is a need for drug forms which release active ingredients in theintestinal tract and moreover comply with specific active ingredientrelease profiles.

The intention was to provide a drug form which releases virtually noactive ingredient in the stomach and enables release of activeingredient which is as uniform and long-lasting as possible both in thesmall intestine and in the large intestinal region. The drug form isintended to be suitable for example for the therapy of inflammatorybowel disorders such as ulcerative colitis and, in particular, Crohn'sdisease.

The object is achieved by a

multiparticulate drug form suitable for uniform release of an activepharmaceutical ingredient in the small intestine and in the largeintestine, comprising at least two forms of pellets A and B whichcomprise an active pharmaceutical ingredient in the core and havedifferent polymer coatings which determine the release of the activeingredient at different pH values,

characterized in that

pellet form A is provided with an inner polymer coating which enablescontinuous release of active ingredient, and has an outer entericcoating which rapidly dissolves above about pH 5.5, and

pellet form B is provided with an inner polymer coating which, in theUSP release test, releases less than 20% of the active ingredient at pH6.8 in 6 hours and releases more than 50% of the active ingredient at pH7.2 in 6 hours.

The invention further relates to a process for producing amultiparticulate drug form by the different pellet forms A and B beingproduced by coating active ingredient-containing cores with the statedpolymer coatings, being mixed together and being converted into amultiparticulate drug form by introduction into a capsule or compressionto a tablet unit in the presence of excipients.

The invention likewise relates to the use of the described pellet formsA and B in the claimed process for producing a multiparticulate drugform with uniform release of active ingredient in the pH range of 6.8and [sic] 7.2, corresponding to the conditions in the small and largeintestine, in particular for the treatment of Crohn's disease orulcerative colitis.

MODE OF OPERATION OF THE INVENTION

The multiparticulate drug form may be in the form of a capsule filledwith pellets, e.g. a gelatin capsule, or it may be a tablet in which thepellets have been compressed together with conventional excipients togive the tablet unit.

The multiparticulate drug form is suitable for substantially uniformrelease of an active pharmaceutical ingredient in the small intestineand in the large intestine and comprises at least two forms of pellets,A and B, which comprise an active pharmaceutical ingredient in the core,but have different polymer coatings which determine the release of theactive ingredient at different pH values. In vitro, the USP release test(USP 23, method 2) results at pH 6.8 and at pH 7.2 in combined profileswhich are between the individual release curves for the two pellet formsA and B. In vivo, the release profile of pellet form A predominates inthe small intestine, and release of active ingredient from pellet form Bstarts while in the large intestinal region.

The pellet cores consist entirely or partly of an active pharmaceuticalingredient. The cores are usually spherical or round and have diametersin the range from about 0.3 to 2 mm. The polymer coatings are in therange from about 2 to 16 mg of polymer per cm² surface area of thecores.

Pellet Form A

Pellet form A is provided with an inner polymer coating and an outerpolymer coating.

Inner Polymer Coating

The inner polymer coating enables substantially pH-independentcontinuous release of active ingredient. The aim is an active ingredientrelease profile with which, in the USP release test (USP 23, method 2),at pH 6.8 there is about 40 to 70%, preferably 40 to 60%, release ofactive ingredient after 2 hours, and 60 to 100%, preferably 80 to 100%release after 4 hours. This is derived from the average residence timein the small intestine, which is about 4 hours.

The inner polymer coating of pellet form A may consist of a(meth)acrylate copolymer, of free-radical polymerized C1- to C4-alkylesters of acrylic or methacrylic acid and (meth)acrylate monomers with aquaternary ammonium group in the alkyl radical.

Appropriate (meth)acrylate copolymers are disclosed, for example, inEP-A 181 515 or DE-C 1 617 751. They are polymers which are soluble orswellable independently of the pH and which are suitable forpharmaceutical coatings. A possible production process to be mentionedis bulk polymerization in the presence of a free-radical initiatordissolved in the monomer mixture. The polymer can likewise also beproduced by a solution or precipitation polymerization. The polymer canbe obtained in this way in the form of a fine powder, which isachievable in the case of bulk polymerization by grinding, and in thecase of solution and precipitation polymerization for example by spraydrying.

The (meth)acrylate copolymer is composed of 85 to 98% by weightfree-radical polymerized C1- to C4-alkyl esters of acrylic ormethacrylic acid and 15 to 2% by weight (meth)acrylate monomers with aquaternary ammonium group in the alkyl radical.

Preferred C1- to C4-alkyl esters of acrylic or methacrylic acid aremethyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate andmethyl methacrylate.

The particularly preferred (meth)acrylate monomer with quaternaryammonium groups is 2-trimethylammonium methyl methacrylate chloride.

A further suitable (meth)acrylate copolymer may be composed, forexample, of 85 to less than 93% by weight C1- to C4-alkyl esters ofacrylic or methacrylic acid and more than 7 to 15% by weight(meth)acrylate monomers with a quaternary ammonium group in the alkylradical. Such (meth)acrylate monomers are commercially available andhave been used for a long time for release-slowing coatings (type(EUDRAGIT® [sic] RL).

A specifically suitable copolymer comprises, for example, 60% by weightmethyl methacrylate, 30% by weight ethyl acrylate and 10% by weight2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® RL).

The desired release characteristics can be achieved for example throughthe thickness of the coating layer of polymer coatings of the “EUDRAGIT®RL type” described above. This is achieved for example with a 5 to 15%coating of EUDRAGIT® RL on active ingredient-containing cores with adiameter of 0.8 to 1.2 mm. The required release characteristics can alsobe achieved with other layer thicknesses by admixing a copolymercomposed of 50-70% by weight methyl methacrylate, 20-40% by weight ethylacrylate and 7-2% by weight 2-trimethylammoniumethyl methacrylatechloride (“EUDRAGIT® RS type”). A specifically suitable polymercomprises 65% by weight methyl methacrylate, 30% by weight ethylacrylate and 5% by weight 2-trimethylammoniumethyl methacrylate chloridebe composed [sic] (EUDRAGIT® RS). The EUDRAGIT® RL and RS types can bemixed for example in the ratios 10:1 to 1:10. Higher proportions of the“EUDRAGIT® RL type” are preferred, e.g. 60 to 90% by weight in themixture.

The inner polymer coating may also consist of a (meth)acrylate copolymercomposed of 20 to 40% by weight ethyl acrylate and 60 to 80% by weightmethyl methacrylate, ethylcellulose or polyvinyl acetate.

Outer Polymer Coating

The outer polymer coating is an enteric coating which rapidly dissolvesonly above about pH 5.5. The coating is thus intended to prevent releaseof active ingredient in the substantially [sic] stomach, i.e. this isintended to be no more than 10, preferably only 5, % according to USP23. On transit into the small intestine it is intended that the outerpolymer layer dissolve rapidly so that the release characteristics fromthis time onwards are determined by the inner polymer coating. If theouter polymer coating is too thin, too much active ingredient isreleased in the stomach. If the outer polymer coating is applied toothickly, it prevents direct release of active ingredient in the smallintestine. Suitable layer thicknesses are, for example, in the rangefrom 15 to 150 μm, preferably, for example, at 20 to 60 μm. Based on theweight of the core provided with the inner polymer coating and having adiameter of from 0.8 to 1.25 mm, it is usually suitable to apply polymer(based on dry matter) in the range from 8 to 40% by weight, preferablyfrom 10 to 25% by weight.

The enteric polymer coating of pellet form A may [lacuna] of a(meth)acrylate copolymer which contains acidic groups and has, forexample, acrylic acid, but preferably methacrylic acid, residues.

The (meth)acrylate copolymer consists of 40 to 100, preferably 45 to 99,in particular 85 to 95, % by weight free-radical polymerized C₁- toC₄-alkyl esters of acrylic or methacrylic acid and may comprise 0 to 60,preferably 1 to 55, in particular 5 to 15, % by weight (meth)acrylatemonomers with an anionic group in the alkyl radical.

C₁- to C₄-alkyl esters of acrylic or methacrylic acid are, inparticular, methyl methacrylate, ethyl methacrylate, butyl methacrylate,methyl acrylate, ethyl acrylate and butyl acrylate.

Suitable examples are also neutral (meth)acrylate copolymers of 20 to40% by weight ethyl acrylate and 60 to 80% by weight methyl methacrylate(EUDRAGIT® NE type) if they are used in a mixture with (meth)acrylatecopolymers containing acidic groups.

Particular suitable (meth)acrylate copolymers are composed of 40 to 60%by weight methacrylic acid and 60 to 40% by weight methyl methacrylateor 60 to 40% by weight ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L100-55types).

Also suitable in principle are anionic (meth)acrylate copolymers of 20to 40% by weight methacrylic acid and 80 to 60% by weight methylmethacrylate (EUDRAGIT® S type).

Also suitable are (meth)acrylate copolymers consisting of 10 to 30% byweight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to15% by weight methacrylic acid (EUDRAGIT® FS type).

The enteric polymer coating of pellet form A may also consist ofshellac, HPMCP (hydroxypropylmethylcellulose phthalate), CAP (celluloseacetate phthalate), HPMC-AS (hydroxypropylmethylcellulose acetatesuccinate) or polyvinyl acetates [sic] phthalate.

However, care must be taken in every case that the coating is adjustedfor example in relation to layer thickness and, where appropriate,mixing with other polymers in such a way that it dissolves rapidly aftertransit into the small intestine.

Pellet Form B

Pellet form B releases, at pH 6.8 in the USP release test (USP 23,method 2), not more than 10%, preferably not more than 5%, after 2 hoursand not more than 20, preferably not more than 10, % of the activeingredient after 4 hours. At pH 7.2, about 40 to 60% of activeingredient are released after 3 hours, and about 80 to 100 [lacuna] arereleased after 60 hours.

The polymer coating for pellet form B may be a (meth)acyrlate [sic]copolymer which is composed of 60 to 95% by weight free radicalpolymerized C₁- to C₄-alkyl esters of acrylic or methacrylic acid and 5to 40% by weight (meth)acrylate monomers with an acidic group in thealkyl radical.

Particular suitable (meth)acrylate copolymers consist of 10 to 30% byweight methyl methacrylate, 50 to 70% by weight methyl acrylate and 5 to15% by weight methacrylic acid (EUDRAGIT® FS type).

Likewise suitable are (meth)acrylate copolymers of 20 to 40% by weightmethacrylic acid and 80 to 60% by weight methyl methacrylate (EUDRAGIT®S type).

Pellet form B is preferably provided with only one polymer coating butmay, if the release profile in the large intestine is to be modified,also, like pellet form A, be provided additionally with an inner polymercoating resulting in a substantially pH-independent continuous releaseof active ingredient. This may be worthwhile if it is necessary toextend the release of active ingredient in the large intestine (colon)to 6 to 12 or up to 24 hours.

Active Ingredients

The formulation of the invention is suitable for the administration of alarge number of active pharmaceutical ingredients which are to bereleased in the small intestine and in the large intestine, and inparticular those active ingredients which can advantageously beadministered in a slow-release form, such as antidiabetics, analgesics,antiinflammatory agents, antirheumatics, antihypotensive agents,antihypertensive agents, psychoactive drugs, tranquillizers,antiemetics, muscle relaxants, glucocorticoids, agents for treatingulcerative colitis or Crohn's disease, antiallergics, antibiotics,antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, proteins, peptides, enzymes,enzyme inhibitors, gout remedies, hormones and inhibitors thereof,cardiac glycosides, immunotherapeutic agents and cytokines, laxatives,lipid-lowering agents, migraine remedies, mineral products, otologicals,anti parkinson agents, thyroid therapeutic agents, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals, chemotherapeutic agents and aminoacids.

Examples of suitable active ingredients are acarbose, antigens,beta-receptor blockers, non-steroidal antirheumatia [sic], cardiacglycosides, acetylsalicylic acid, virustatics, aclarubicin, acyclovir,cisplatin, actinomycin, alpha- and beta-sympatomimetics [sic],(dmeprazole [sic], allopurinol, alprostadil, prostaglandins, amantadine,ambroxol, amlodipine, methotrexate, S-aminosalicylic acid [sic],amitriptyline, amoxicillin, anastrozole, atenolol, azathioprine,balsalazide, beclomethasone, betahistine, bezafibrate, bicalutamide,diazepam and diazepam derivatives, budesonide, bufexamac, buprenorphine,methadone, calcium salts, potassium salts, magnesium salts, candesartan,carbamazepine, captopril, cefalosporins, cetirizine, chenodeoxycholicacid, ursodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clarithromycin, clavulanic acid, clindamycin,clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D andderivatives of vitamin D, colestyramine, cromoglicic acid, coumarin andcoumarin derivatives, cysteine, cytarabine, cyclophosphamide,ciclosporin, cyproterone, cytarabine [sic], dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulphoxide, dimeticone, dipyridarnoi [sic], domperidone anddomperidan [sic] derivatives, dopamine, doxazosin, doxorubizin [sic],doxylamine, dapiprazole [sic], benzodiazepines, diclofenac, glycosideantibiotics, desipramine, econazole, ACE inhibitors, enalapril,ephedrine, epinephrine, epoetin and epoetin derivatives, morphinans,calcium antagonists, irinotecan, modafinil, orlistat, peptideantibiotics, phenytoin, riluzoles, risedronate, sildenafil, topiramate,macrolide antibiotics, oestrogen and oestrogen derivatives, progestogenand progestogen derivatives, testosterone and testosterone derivatives,androgen and androgen derivatives, ethenzamide, etofenamate, etofibrate,fenofibrate, etofylline, etoposide, famciclovir, famotidine, felodipine,fenofibrate, fentanyl, fenticonazole, gyrase inhibitors, fluconazole,fludarabine, fluarizine, fluorouracil, fluoxetine, flurbiprofen,ibuprofen, flutamide, fluvastatin, follitropin, formoterol, fosfomicin,furosemide, fusidic acid, gallopamil, ganciclovir, gemfibrozil,gentamicin, ginkgo, Saint John's wort, glibenclamide, urea derivativesas oral antidiabetics, glucagon, glucosamine and glucosaminederivatives, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, goserelin, gyrase inhibitors [sic], guanethidine,halofantrine, haloperidol, heparin and heparin derivatives, hyaluronicacid, hydralazine, hydrochlorothiazide and hydrochlorothiazidederivatives, salicylates, hydroxyzine, idarubicin, ifosfamide,imipramine, indometacin, indoramine, insulin, interferons, iodine andiodine derivatives, isoconazole, isoprenaline, glucitol and glucitolderivatives, itraconazole, ketoconazole, ketoprofen, ketotifen,lacidipine, lansoprazole, levodopa, levomethadone, thyroid hormones,lipoic acid and lipoic acid derivatives, lisinopril, lisuride,lofepramine, lomustine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mepindolol, meprobamate, meropenem, mesalazine, mesuximide,metamizole, metformin, methotrexate, methylphenidate,methylprednisolone, metixene, metoclopramide, metoprolol, metronidazole,mianserin, miconazole, minocycline, minoxidil, misoprostol, mitomycin,mizolastine, moexipril, morphine and morphine derivatives, eveningprimrose, nalbuphine, naloxone, tilidine, naproxen, narcotine,natamycin, neostigmine, nicergoline, nicethamide, nifedipine, niflumicacid, nimodipine, nimorazole, nimustine, nisoldipine, adrenaline andadrenaline derivatives, norfloxacin, novamine sulfone, noscapine,nystatin, ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole,ondansetron, oxaceprol, oxacillin, oxiconazole, oxymetazoline,pantoprazole, paracetamol, paroxetine, penciclovir, oral penicillins,pentazocine, pentifylline, pentoxifylline, perphenazine, pethidine,plant extracts, phenazone, pheniramine, barbituric acid derivatives,phenylbutazone, phenytoin, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,prostaglandins [sic], protionamide, proxyphylline, quetiapine,quinapril, quinaprilat, ramipril, ranitidine, reproterol, reserpine,ribavirin, rifampicin, risperidone, ritonavir, ropinirole, roxatidine,roxithromycin, ruscogenin, rutoside and rutoside derivatives, sabadilla,salbutamol, salmeterol, scopolamine, selegiline, sertaconazole,sertindole, sertralion [sic], silicates, sildenafil [sic], simvastatin,sitosterol, sotalol, spaglumic acid, sparfloxacin, spectinomycin,spiramycin, spirapril, spironolactone, stavudine, streptomycin,sucralfate, sufentanil, sulbactam, sulphonamides, sulfasalazine,sulpiride, sultamicillin, sultiam, sumatriptan, suxamethonium chloride,tacrine, tacrolimus, taliolol, tamoxifen, taurolidine, tazarotene,temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline,terfenadine, terlipressin, tertatolol, tetracyclins, teryzoline,theobromine, theophylline, butizine, thiamazole, phenothiazines,thiotepa, tiagabine, tiapride, propionic acid derivatives, ticlopidine,timolol, tinidazole, tioconazole, tioguanine, tioxolone, tiropramide,tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone,topotecan, torasemide, antioestrogens, tramadol, tramazoline,trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone andtriamcinolone derivatives, triamterene, trifluperidol, trifluridine,trimethoprim, trimipramine, tripelennamine, triprolidine, trifosfamide,tromantadine, trometamol, tropalpin, troxerutine, tulobuterol, tyramine,tyrothricin, urapidil, ursodeoxycholic acid [sic], chenodeoxycholic acid[sic], valaciclovir, valproic acid, vancomycin, vecuronium chloride,Viagra, venlafaxine, verapamil, vidarabine, vigabatrin, viloazine,vinblastine, vincamine, vincristine, vindesine, vinorelbine,vinpocetine, viquidil, warfarin, xantinol nicotinate, xipamide,zafirlukast, zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicone[sic], zotipine and the like.

The active ingredients may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives, and in the caseof chiral active ingredients it is possible to employ both opticallyactive isomers and racemates or mixtures of diastereoisomers. Ifdesired, the compositions of the invention may also comprise two or moreactive pharmaceutical ingredients.

Active ingredients which have been mentioned in particular as suitablefor the therapy of ulcerative colitis and Crohn's disease are thosewhich are intended to be released as constantly as possible in theintestine, in particular shortly before or only in the large intestinalregion. The active pharmaceutical ingredient may be an aminosalicylate,a sulphonamide or a glucocordicoid and those which should beparticularly mentioned are 5-aminosalicylic acid, olsalazine,sulfalazine [sic], prednisone or budesonide.

The following table summarizes active ingredients suitable for thetherapy of ulcerative colitis and Crohn's disease.

Active Ingredients for the Therapy of Ulcerative Colitis

-   mesalazine-   sulfasalazine-   betamethasone 21-dihydrogenophosphate-   hydrocortisone 21-acetate-   cromoglicic acid-   dexamethasone-   olsalazine Na-   budesonide-   bismuitrate, karaya gum-   methylprednisolone 21-hydrogensuccinate-   prednisone-   myhrr, coffee charcoal, camomile flower extract-   10% suspension of human placenta    Other Suitable Active Ingredients-   balsalazide-   orally administered peptides (e.g. RDP 58)-   interleukin 6-   interleukin 12-   ilodecakin (interleukin 10)-   nicotine tartrate-   5-ASA conjugates (CPR 2015)-   monoclonal antibodies against interleukin 12-   diethyldihydroxyhomospermine (DEHOHO)-   diethylhomospermine (DEHOP)-   cholecystokinin (CCK) antagonist (CR 1795)-   15 amino acid fragment of a 40 kd peptide from gastric-   juice (BPC 15)-   glucocorticoid analogue (CBP 1011)-   natalizumab-   infliximab (REMICADE)-   N-deacetylated lysoglycosphingolipid (WILD 20)-   azelastines-   tranilast-   sudismase-   phosphorothioate antisense oligonucleotide (ISIS 2302)-   tazofelones-   ropivacaines-   5 lipoxygenase inhibitor (A 69412)-   sucralfate    Administration Forms

The described (oral) drug form may be in the form of a tablet made fromcompressed pellets or in the form of pellets which are packed in acapsule, e.g. composed of gelatin, starch or cellulose derivatives.

Excipients Customary in Pharmacy

Excipients customary in pharmacy can be employed in a manner known perse in the production of the drug form. These excipients may be presentin the core or in the coating agent.

Dryers (non-stick agents): Dryers have the following properties: theyhave large specific surface areas, are chemically inert, arefree-flowing and comprise fine particles. Because of these properties,they reduce the tack of polymers containing polar comonomers asfunctional groups. Examples of dryers are: alumina, magnesium oxide,kaolin, talc, silica (Aerosils), barium sulphate and cellulose.

Release Agents

Examples of release agents are: esters of fatty acids or fatty amides,aliphatic, long-chain carboxylic acids, fatty alcohols and their esters,montan waxes or paraffin waxes and metal soaps; particular mentionshould be made of glycerol mono-stearate, stearyl alcohol, glycerolbehenic acid ester [sic], cetyl alcohol, palmitic acid, canauba [sic]wax, beeswax, etc. The usual proportionate amounts are in the range from0.05% by weight to 5, preferably 0.1 to 3, % by weight based on thecopolymer.

Other excipients customary in pharmacy: Mention should be made here of,for example, stabilizers, colorants, antioxidants, wetting agents,pigments, gloss agents etc. They are used in particular as processingaids and are intended can be [sic] to ensure a reliable and reproducibleproduction process and good long-term storage stability. Furtherexcipients customary in pharmacy may be present in amounts from 0.001%by weight to 100% by weight, preferably 0.1 to 10% by weight, based onthe polymer coating.

Plasticizers: Substances suitable as plasticizers ordinarily have amolecular weight between 100 and 20 000 and comprise one or morehydrophilic groups in the molecule, e.g. hydroxyl, ester or aminogroups. Citrates, phthalates, sebacates, castor oil are suitable.Examples of suitable plasticizers are alkyl citrates, glycerol esters,alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters,dibutyl sebacate and polyethylene glycols 4000 to 20000. Preferredplasticizers are tributyl citrate, triethyl citrate, acetyl triethylcitrate, dibutyl sebacate and diethyl sebacate. The amounts used arebetween 1 and 35, preferably 2 to 10, % by weight % [sic], based on the(meth)acrylate copolymer.

Active Ingredient-Containing Pellets

Active ingredient-containing pellets can be produced by applying activeingredient by means of a layering process. This is done by homogenizingactive ingredient together with other excipients (release agents, whereappropriate plasticizers) and dissolving or suspending in a binder (e.g.EUDRAGIT L 30 D-55). A fluidized bed process can be used to apply theliquid to placebo pellets or other suitable carrier materials, withevaporation of the solvent or suspending agent (literature:International Journal of Pharmaceutics 143, pp. 13-23). The productionprocess may be followed by a drying step. The active ingredient may beapplied in a plurality of layers.

An alternative possibility is to produce active ingredient-containingpellets by an extrusion/spheronization process. This can be carried outfor example as follows: lactose (20%) and active ingredient (80%;mesalazine=5-ASA) were mixed in a high speed mixer (DIOSNA type P10,Osnabrück, Germany), and an aqueous solution containing the excipientKollidon 25 was added in small amounts until a homogeneous compositionwas obtained. The moist powder mixture was screened. Pellets weresubsequently shaped therefrom with the aid of a type 15 Spheronizer(Caleva, Ascot, UK).

The coating with the FS [sic] polymer took place in a Glatt coater (WSG5or GPCG1 type, Glatt GmbH, Binzen/Lörrach, Germany). A 20% layer (basedon dry weight) was applied to the pellets using the top spray method ina manner conventional per se.

Some active ingredients, e.g. acetylsalicylic acid, are commerciallyavailable in the form of active ingredient crystals and can be employedin this form in place of active ingredient-containing pellets.

Film coatings of active ingredient-containing pellets are normallyapplied in fluidized bed equipment. Examples of formulations arementioned in this application. Film formers are normally mixed withplasticizers and release agents by a suitable process. The film formersmay in this case be in the form of a solution or suspension. Theexcipients for the film formation may likewise be dissolved orsuspended. Organic or aqueous solvents or dispersants can be used.Stabilizers can be used in addition to stabilize the dispersion (forexample: Tween 80 or other suitable emulsifiers or stabilizers).

Examples of release agents are glycerol monostearate or other suitablefatty acid derivatives, silicic acid derivatives or talc. Examples ofplasticizers are propylene glycol, phthalates, polyethylene glycols,sebacates or citrates, and other substances mentioned in the literature.

General conditions for the release tests (e.g. USP 23): pH 1.2:simulated gastric fluid without pepsin (SGF-sp), pH 6.8 and pH 7.2:phosphate buffer complying with DAB 10. ERWEKA type DT 80 apparatus“(paddle) [sic]; 900 ml of test medium at 37° C., 100 rpm. The testswere each carried out in triplicate.

Production of Multiparticulate Drug Forms

The multiparticulate drug form is produced by mixing the differentpellet forms A and B, e.g. in the ratio 1:1 or another ratio, dependingon the amount of active ingredient present, packing in a capsule or bycompression to a tablet unit in the presence of excipients into themultiparticulate drug form.

The production of multiparticulate drug forms by compression of a binderwhich is customary in pharmacy with active ingredient-containingparticles is described in detail for example [lacuna] Beckert et al.(1996) “Compression of enteric-coated pellets to disintegratingtablets”, International Journal of Pharmaceutics 143, pp. 13-23, and inWO 96/01624.

Mixtures for producing tablets from coated particles are prepared bymixing the pellets with suitable binders for tabletting, if necessaryadding disintegration-promoting substances and if necessary addinglubricants. The mixing can take place in suitable machines. Unsuitablemixers are those which lead to damage to the coated particles, e.g.ploughshare mixers. A special sequence of addition of the excipients tothe coated particles may be necessary to achieve suitable shortdisintegration times. Premixing with [sic] the coated particles with thelubricant or mould release agent magnesium stearate is able to renderits [sic] surface hydrophobic and thus avoid sticking.

Mixtures suitable for tabletting normally comprise 3 to 15% by weight ofa disintegration aid, e.g. Kollidon C L, and e.g. 0.1 to 1% by weight ofa lubricant and mould release agent such as magnesium stearate. Thebinder content is determined by the required content of coatedparticles.

Typical binders are, for example, Cellactose®, micro-cyrstallinecellulose, calcium phosphates, Ludipress®, lactose or other suitablesugars, calcium sulphates or starch derivatives. Substances of low bulkdensity are preferred.

Typical disintegration aids (disintegrants) are crosslinked starchderivatives or cellulose derivatives, and crosslinkedpolyvinylpyrrolidone. Cellulose derivatives are likewise suitable. Theuse of disintegration aids may be omitted through selection of asuitable binder.

Typical lubricants and mould release agents are magnesium stearates orother suitable salts of fatty acids or substances detailed in theliterature for this purpose (e.g. lauric acid, calcium stearate, talcetc.). The use of a lubricant and mould release agent in the mixture canbe omitted if suitable machines (e.g. tablet press with externallubrication) or suitable formulations are used.

The mixture may where appropriate be admixed with an aid to improve flow(e.g. highly disperse silica derivatives, talc etc.).

The tabletting can take place in conventional tablet presses, eccentricor rotary tablet presses, with compressive forces in the range from 5 to40 kN, preferably 10-20 kN. The tablet presses may be equipped withsystems for external lubrication. Special systems for die filling whichavoid die filling by means of agitator blades are employed whereappropriate.

The application rate means the proportion of dry substance of thefunctional film-forming polymer sprayed on in % by weight. It is above15 to 38, particularly preferably 18 to 36, in particular 20 to 30, % byweight based on the particle weight.

The particle content means the weight of the coated particles as aproportion of the total weight of the drug form, the compressed table[sic], in % by weight. The particle content of the drug form is 35-90,particularly preferably 40 to 70, % by weight. Particle contents of from70 to 90% by weight can be achieved in particular by employing so-calledsoft cores in place of sugar pellets.

EXAMPLES Example 1

Pellet Form A, Inner Polymer Coating

Commercially available cores comprising the active ingredient5-aminosalicylic acid, with a diameter in the range from 0.8 to 1.25 mm,are coated with a 12% coating of a copolymer of 60% by weight methylmethacrylate, 30% by weight ethyl acrylate and 10% by weight2-trimethylammoniumethyl methacrylate chloride (EUDRAGIT® RL).

For this purpose, 30 g of talc, 12 g of triethyl citrate and 268 g ofwater are added to 200 g of a 30% strength dispersion of the copolymer(EUDRAGIT® RL 30D) (solids content 20.4 5 [sic]). The cores are coatedin a fluidized bed apparatus (STREA 1, Aeromatic-Fielder AG, Bubendorf,Switzerland) with a nozzle arrangement in the bottom-spray mode and anozzle diameter of 0.8 mm and a spraying pressure of 1.4 to 1.5 bar. 500g of pellets, air inlet temperature 32-36° C., air outlet temperature25-30° C., spraying rate 2.4 g/min.

Example 2

Pellet Form A, Outer Polymer Coating

The coated cores from Example 1 are [lacuna] with an outer polymercoating of a (meth)acrylate copolymer of 50% by weight methacrylic acidand 50% by weight ethyl acrylate (EUDRAGIT® L100-55 or DispersionEUDRAGIT® L 30 D-55)

For this purpose, 25 g of talc, 5 g of triethyl citrate and 204 g ofwater are added to 166 g of a 30% strength dispersion of theabovementioned copolymer (EUDRAGIT® L30D-55) (solids content 20.4%). Thecores are coated as indicated in Example 1 in the fluidized bedapparatus. 20% polymer (polymer dry substance relative to the coatedpellet) is applied by spraying.

Example 3

Pellet Form B

Active ingredient-containing pellets are coated as in Example 1 but witha (meth)acrylate copolymer consisting of 25% by weight methylmethacrylate, 65% by weight methyl acrylate and 10% by weightmethacrylic acid (EUDRAGIT® FS).

For this purpose, 4 g of glycerol monostearate, 2 g of polysorbate 80,2.5 g of triethyl citrate and 185 g of water are added to 166 g of a 30%strength dispersion of the abovementioned copolymer (EUDRAGIT® FS 30 D)(solids content of the spray dispersion 20%). The cores are coated asindicated in Example 1 in the fluidized bed apparatus. 20% polymer(polymer dry substance relative to the coated pellet) is applied byspraying.

Example 4

Formula for a Multiparticulate Drug Form Composed of Pellet Forms A andB as in Examples 2 and 3.

Tablet formulation Pellet form A 250.0 g Pellet form B 250.0 gCellactose 417.5 g Kollidon CL  80.0 g Magnesium stearate  2.5 g

The mixture can be compressed to tablets directly in a suitable tabletpress using, for example, a compressive force of 15 kN.

1. A multiparticulate drug form comprising at least pellet form A andpellet form B, wherein each of said pellet forms comprises an activepharmaceutical ingredient and at least one polymer coating, wherein thepolymer coating of pellet form A is different from the polymer coatingof pellet form B, wherein pellet form A comprises an inner polymercoating and an outer enteric coating which rapidly dissolves above aboutpH 5.5, and pellet form B comprises a different polymer coating which,in the USP release test, releases less than 20% of the activepharmaceutical ingredient at pH 6.8 in 6 hours and releases more than50% of the active pharmaceutical ingredient at pH 7.2 in 6 hours,wherein said multiparticulate drug form is capable of uniformlyreleasing the active pharmaceutical ingredient in the small intestineand large intestine, and wherein the polymer coating of pellet form Aand pellet form B determines the release of the active pharmaceuticalingredient at different pH, wherein the active pharmaceutical ingredientis an aminosalicylate, a sulphonamide, a hormone, a peptide, aninterferon, or a glucocorticoid.
 2. The multiparticulate drug formaccording to claim 1, wherein the enteric polymer coating of pellet formA comprises an acidic group-containing (meth)acrylate copolymer,shellac, HPMCP (hydroxypropylmethylcellulose phthalate), CAP (celluloseacetate phthalate), HIPMC-AS (hydroxypropylmethylcellulose acetatesuccinate) or polyvinyl acetate phthalate.
 3. The multiparticulate drugform according to claim 2, wherein the enteric polymer coating is a(meth)acrylate copolymer comprising 40 to 60% by weight of polymerizedmethacrylic acid and 60 to 40% by weight ofpolymerized methylmethacrylate or ethyl acrylate.
 4. The niultiparticulate drug formaccording to claim 1, wherein the inner polymer coating of pellet form Acomprises a (meth)acrylate copolymer comprising free-radical polymerizedC₁- to C₄-alkyl esters of acrylic or methacrylic acid and (meth)acrylatemonomers with a quatemary anunonium group in the alkyl radical, a(meth)acrylate copolymer of 20 to 40% by weight of polymerized ethylacrylate and 60 to 80% by weight of polymerized methyl methacrylate,ethylcellulose or polyvinyl acetate.
 5. The multiparticulate drug formaccording to claim 4, wherein the inner polymer coating of pellet form Acomprises a (meth)acrylate copolymer of 85 to less than 93% by weight ofpolymerized units of C₁- to C₄-alkyl esters of acrylic or methacrylicacid and more than 7 to 15% by weight of polymerized (meth)acrylatemonomers with a quaternary animonium group in the alkyl radical.
 6. Themultiparticulate drug form according to claim 1, wherein the differentpolymer coating of pellet form B comprises a (meth)acrylate copolymercomprising 60 to 95% by weight free-radical polymerized C₁- to C₄-alkylesters of acrylic or methacrylic acid and 5 to 40% by weight(meth)acrylate monomers with an acidic group in the alkyl radical. 7.The multiparticulate drug form according to claim 6, wherein thedifferent polymer coating of pellet form B comprises a (meth)acrylatecopolymer comprising 10 to 30% by weight of polymerized units of methylmethacrylate, 50 to 70% by weight methyl acrylate and 5 to 15% by weightmethacrylic acid.
 8. The multiparticulate drug form according to claim6, wherein pellet form B further comprises an inner polymer coating. 9.The multiparticulate drug form according to claim 1, wherein the activepharmaceutical ingredient is 5-aminosalicylic acid, olsalazine,sulfalazine, prednisone or budesonide.
 10. A process for producing themultiparticulate drug form according to claim 1, comprising coatingcores comprising at least one active pharmaceutical ingredient with aninner polymer coating and an outer enteric coating to form pellet formA, coating cores comprising at least one active pharmaceuticalingredient with at least one different polymer coating to form pelletform B, mixing said pellet forms A and B, and forming themultiparticulate drug form by introducing the mixed pellet forms A and Binto a capsule or compressing the mixed pellet forms A and B in thepresence of one or more excipients.
 11. The multiparticulate drug formaccording to claim 1, wherein the multiparticulate drug form is capableof uniformly releasing the active ingredient in a pH range of from 6.8to 7.2.
 12. The multiparticulate drug form according to claim 1, whereinthe multiparticulate drug form is capable of treating Crohn's disease orulcerative colitis.
 13. The multiparticulate drug form according toclaim 1, wherein each of said pellet forms A and B comprise the sameactive pharmaceutical ingredient.
 14. The process according to claim 10,wherein each of said pellet forms A and B comprise the same activepharmaceutical ingredient.
 15. A method comprising administering anactive pharmaceutical ingredient to a human, wherein the activepharmaceutical ingredient is released in the small intestine and thelarge intestine, wherein the active pharmaceutical ingredient is presentin a multiparticulate drug form comprising at least pellet form A andpellet form B, wherein the pellet form A comprises an inner polymercoating and an outer enteric coating which rapidly dissolves above aboutpH 5.5, and wherein pellet form B comprises a polymer coating whichreleases less than 20% of the active pharmaceutical ingredient at a pHof 6.8 in 6 hours and releases more than 50% of the active ingredient ata pH of 7.2 in 6 hour, wherein the polymer coating of pellet form A isdifferent from the polymer coating of pellet form B, and wherein theactive pharmaceutical ingredient is an aminosalicylate, a suiphonamide,a hormone, a peptide, an interferon, or a glucocorticoid.
 16. The methodof claim 15, wherein an active pharmaceutical ingredient is administeredto treat Crohn's disease or ulcerative colitis.
 17. The method accordingto claim 15, wherein each of said pellet forms A and B comprise the sameactive pharmaceutical ingredient.